3-aryl-5-alkylthio-4H-1,2,4-triazoles

ABSTRACT

This invention relates to novel sulfone and sulfoxide derivatives of 3-aryl-5-alkylthio-4H-1,2,4-triazoles and to the use of 3-aryl-5-alkylthio-, alkylsulfinyl- and alkylsulfonyl-4H-1,2,4-triazoles in the treatment of patients suffering from convulsant seizures.

This is a division of application Ser No. 07/770,837, filed Oct. 4,1991, now U.S. Pat. No. 5,143,933, which is a continuation-in-part ofcopending application Ser. No. 07,630,659, filed Dec. 20, 1990, nowabandoned, which is a continuation-in-part of application Ser. No.07/463,082, filed Jan. 10, 1990, now U.S. Pat. No. 4,981,863, which is adivision of application Ser. No. 07/126,191, filed Dec. 4, 1987, nowU.S. Pat. No. 4,900,743, which is a continuation-in-part of applicationSer. No. 07/007,063, filed Jan. 27, 1987, now abandoned.

SUMMARY OF THE INVENTION

This invention relates to derivatives of3-aryl-5-alkylthio-4H-1,2,4-triazoles and their use in the treatment ofpatients suffering from muscle tension, muscle spasms and the painassociated therewith, chronic hyperreflexia due to spinal trauma,convulsant seizures and anxiety.

More specifically this invention relates to the use of compounds offormula I ##STR1## wherein Ar is phenyl or naphthyl;

R₁ is C₁₋₋₆ lower alkyl;

R₂ is hydrogen or C₁₋₋₆ lower alkyl;

R is C₁₋₋₆ lower alkyl, C₁₋₋₆ alkoxy, hydroxy, halogeno, ortrifluoromethyl and n is zero, 1 or 2, or R_(n) --(Ar) ismethylenedioxyphenyl; and each of m and q is zero, 1 or 2;

and their pharmaceutically acceptable salts as muscle relaxants,antispastics, anticonvulsants and anxiolytics.

Another aspect of this invention relates to novel5-aryl-3-alkylsulfinyl-4H-1,2,4-triazoles of formula II, ##STR2##wherein Ar, R₁, R₂, R, m and n have the meanings defined above.

Another aspect of this invention relates to novel5-aryl-3-alkylsulfonyl-4H-1,2,4-triazoles of formula III, ##STR3##wherein Ar, R₁, R₂, R, m and n have the meanings defined above, with theprovisos that (1) R_(n) --Ar--(CH₂)_(m) is other than 2-ethoxyphenyl;that (2) when R₂ --(Ar)--(CH₂)_(m) is phenyl and R₁, is methyl, R₂ isC₁₋₋₆ lower alkyl; and that (3) when R_(n) --(Ar)--(CH₂)_(m) represents4-chlorophenyl, R₂ is other than ethyl.

DETAILED DESCRIPTION OF THE INVENTION

In Formulas I, II and III, halogeno preferably represents chloro orfluoro, and methyl and ethyl are the preferred lower alkyl moieties,although all the straight and branched manifestations thereof areincluded. Lower alkoxy radicals include ethers having alkyl moietiesparalleling the C₁₋₋₆ alkyl group. When "Ar" is phenyl, n is preferablyone, representing a mono-substituted phenyl moiety with theR-substituent being a group located at any of the ortho, meta or parapositions. When n is 2, the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-positions are contemplated. Preferably R₁, and R2 each represents methylor ethyl.

State of the art salts of these triazoles may be employed, with thehydrochloride being one of convenience and general applicability. Thesesalts are formed by standard techniques well known in the art.

When "Ar" represents naphthyl, the naphthyl ring system can be bondedthrough the 1- or 2- position and the R moiety can be attached theretoat any of the available positions.

The thioethers of Formula I may be prepared using processes andprocedures analogously known in the art as depicted in Reaction SchemeA, wherein R₁, R2 and R_(n) --(Ar)--(CH₂)_(m) are as defined for FormulaI, and X is a suitable leaving group. ##STR4##

The sulfoxides and sulfones of Formula I may be prepared by oxidizingthe alkylthioethers of Formula Ia with a peracid, preferablyM-chloroperoxybenzoic acid (MCPBA), as seen in the following ReactionScheme B, wherein, R₁, R₂ and R_(n) --(Ar)--(CH₂)_(m) are as defined forFormula I. ##STR5##

The preparation of the R₂ -substituted thiosemicarbaides (IV) is readilyeffected by reacting hydrazine with an isothiocyanate in a suitablesolvent. The reaction is quite rapid and may be carried out between 0° Cand room temperature. Although the reaction proceeds rapidly, themixture may be left for up to 24 hours without significant decrease inyield. Reflux conditions may be employed but are not preferred. Almostall solvents may be used. Alcohols (preferably ethanol or methanol) arepreferred, although dimethylformamide (DMF), CHCl₃, CH₂ Cl₂,tetrahydrofuran (THF) and Et₂ may also be used. The requiredisothiocyanates are generally commercially available but may also beprepared by known techniques quite obvious to one of ordinary skill inthe art. Once obtained, the thiosemicarbazides are converted to theircorresponding aroyl-substituted thiosemicarbazides (VI) by reaction withan appropriate acid chloride (V) in an aprotic solvent such as pyridine,CHCl₃, THF, and the like. The acylation proceeds rather easily attemperatures ranging from 0° C to room temperature over periods of 3 to24 hours, although elevated temperatures (e.g., reflux temperatures) maybe employed. Alternatively, aroyl-substituted thiosemicarbazides (VI)may also be prepared by reacting carboxylic acid hydrazides (VII) andisothiocyanates (VIII) in an aprotic solvent such as THF, CHCl₃, CH₂Cl₂, and the like. Again, the acid halides (V) and acid hydrazides (VII)are often commercially available, but may also be prepared from thecorresponding acids which are generally commercially available.

The aroyl thiosemicarbazides (VI) are subjected to a cyclizationreaction which yields 3-aryl-3H-1,2,4-triazole-5-thiones of formula IX.The cyclization reaction is effected by heating the compounds (VI) in anaqueous base such as sodium bicarbonate or sodium hydroxide. Alcoholicbases may be utilized but generally are less desirable. The reaction isconducted at about the reflux temperature of the solvent, preferably atabout 65°-100° C.

The preparation of the alkylthioethers (la) is readily effected bystandard alkylation procedures. Preferably the3-aryl-3H-1,2,4-triazole-5-thiones (IX) are reacted with the appropriatealkyl halide (R₁,X) or a functional equivalent thereof in the presenceof a mild base. Suitable bases are alkali metal carbonates orbicarbonates or alkali metal hydroxides, with K₂ CO₃ or aqueous NaOHbeing preferred. It is preferred to use an alkyl iodide for thealkylation reaction, but any suitable leaving group (e.g., bromideor--OSO₂ CF₃) may be used instead of the iodide. Suitable solvents areacetone, aqueous ethanol, tetrahydrofuran (THF), pyridine, and the like.The reaction may be carried out at temperatures ranging from roomtemperature to the reflux temperature of the reaction mixture, and ingeneral the reaction takes about 15 hours or longer.

The conversion of the 3-aryl-4-alkyl-5-alkylthio-4H-1,2,4-triazoles (Ia)to their higher oxidation state is preferably effected by oxidizing thealkylthioethers (Ia) with a peracid according to well known conditions.Suitable oxidizing agents are H₂ H₂ and NaIO₄, but m-chloroperoxybenzoicacid is preferred. In effecting the oxidation to the sulfinylderivatives of Formula Ib, 1 molar equivalent of the peracid is usedwhile 2 equivalents of the peracid will yield the sulfonyl derivativesof Formula Ic. The oxidations are carried out at temperatures of about0° C. to room temperature in solvents which themselves are notsusceptible to oxidation. Preferred solvents are CH₂ Cl₂, CHCl₃, andacetic acid.

Thioethers of Formula Ia have previously been found to be useful aspesticides, bactericides and fungicides, but have not previously beenshown to possess muscle relaxant, antispastic, anticonvulsant oranxiolytic activity.3-(4-Chlorophenyl)-4-ethyl-5-methylsulfonyl-4H-1,2,4-triazole was foundby M. Y. Mhasalkar, et al. (J. Med 14(3), 260-2 (1971)), to havehypoglycemic activity, but neither that compound nor other sulfones ofFormula Ic have previously been reported to have muscle relaxant,antispastic, anticonvulsant or anxiolytic activity.

It has now been discovered that previously known thioethers and sulfonesof Formula I, as well as the novel sulfoxides and sulfones of FormulasII and III, exhibit pharmacological effects generally attributed tomuscle relaxants, antispastics, anticonvulsants and anxiolytics, andthus the compounds of this invention will provide relief in patientssuffering from muscle tension, muscle spasms and the pain associatedtherewith, convulsant seizures and anxiety. The compounds of thisinvention are also useful in treating hyperreflexia resulting fromspinal injury, as claimed in copending application Ser. No. 630,666,filed Dec. 20, 1990.

Compounds that antagonize the tonic extensor seizures caused bystrychnine have been shown to have muscle relaxant, antispastic,anticonvulsant and anxiolytic activities in man. The activity of thecompounds can be demonstrated by the method of R. A. Turner, ScreeninqMethods in Pharmacology, Chapter 14 (Academic Press, 1965). Groups of 10to 20 male mice are administered one or more doses of test compound inan appropriate vehicle or, for comparison, the vehicle alone. At aselected time thereafter, strychnine sulfate, prepared as a solution indistilled water, is administered intraperitoneally at a dose of 2.7mg/kg. Ninety-nine percent of vehicle-treated mice exhibit convulsionsat this dose of strychnine. Absence of tonic extension for greater than15 minutes after strychnine administration is considered significantprotection.

Treatment of mice with a dosage range of baclofen, a knownantispastic/muscle relaxant, of from 12.5 to 200 mg/kg i.p. causes over50% antagonism of strychnine-induced seizures, but no dose causes 100%protection. Tizanidine, a known muscle relaxant, causes maximalprotection of 60% at 3.1 mg/kg i.p., but doses of up to 50 mg/kg do notcause a greater effect. Diazepam, a known anxiolytic with musclerelaxant and anticonvulsant activity, causes a dose-related inhibitionwith an ED₅₀ of 1.2 mg/kg i.p.; however very high doses are required fortotal inhibition of strychnineinduced seizures. In contrast, many of thecompounds of the present invention protect 100% againststrychnine-induced seizures at doses in the range of 4 times the ED₅₀.Among the compounds of this invention, the intraperitoneallyadministered ED₅₀ is 14.4 mg/kg for4-methyl-3-phenyl-5-ethylsulfinyl-4H-1,2,4-triazole; 19.3 mg/kg for4-methyl-3-phenyl-5-ethylsulfonyl-4H-1,2,4-triazole; 12.8 mg/kg for4-methyl-3-phenyl-5-methylsulfonyl- 4H-1,2,4-triazole; and 18.6 mg/kgfor 4-methyl-3-(2-fluorophenyl)-5-ethylthio-4H-1,2,4-triazole; while theorally administered ED₅₀ is 8.1 mg/kg for4-methyl-3-phenyl-5-ethylsulfinyl-4H-1,2,4-triazole; 8.5 mg/kg for4-methyl-3-phenyl-5-ethylsulfonyl-4H-1,2,4-triazole; 7.3 mg/kg for4-methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole; and 15.1 mg/kg for4-methyl-3-(2-fluorophenyl)-5-ethylthio-4H-1,2,4-triazole.

Injuries to the spinal cord produce a form of muscle spasticity known ashyperreflexia, which can be reduced by treatment with compounds such asclonidine, as described in animals by L. E. Tremblay and J. J. Bedard(Neuropharmacology 25 (1986), 41-46) and in humans by P. W. Nance, A.H.Shears and D. M. Nance (Paraplegia 27 (1989), 296-301). The use ofclonidine for this indication is impractical, however, because ofclonidine's well-known blood pressure lowering effect and CNS depressantaction. Compounds of this invention are useful for treating chronichyperreflexia without such side effects. The effectiveness of thecompounds of this invention for treating muscle spasticity resultingfrom spinal trauma was tested in rats with heightened spontaneous hindlimb movements. Four to six weeks before testing, anesthetized rats werespinally transected at the mid-thoracic level, resulting in this form ofspontaneous limb activity.4-Methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole or clonidine weregiven intraperitoneally, and after 30-minutes reflex activity wasmeasured in treated animals and untreated controls by a computerizedapparatus designed to record, integrate and analyze this activity. Asshown in Table I, below, substantial reduction in muscle spasticity wasseen in rats treated with more than 5 mg/kg of4-methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole or 3.1 μg/kg ofclonidine.

                  TABLE I                                                         ______________________________________                                        4-Methyl-3-phenyl-5-                                                          methylsulfonyl-4H-1,2,4-                                                      triazole          Clonidine                                                   Dosage, Integrated Activity,                                                                        Dosage,  Integrated Activity,                           mg/kg, ip                                                                             % of Control  μg/kg, ip                                                                           % of Control                                   ______________________________________                                        5.0     137 ± 10   3.1      130.2 ± 43.9                                10.0    42.9 ± 12.7                                                                              12.5     50.4 ± 9.8                                  20.0    75.3 ± 19.3                                                                              50.0     32.5 ± 9.5                                  40.0    51.3 ± 11.9                                                        ______________________________________                                    

By contrast, reflex activity induced bu pulling one hindlimb was notreduced by the test compounds, suggesting that compounds of thisinvention have a relatively selective action on the spontaneous activitywithout generally affecting reflex mechanisms.

In their use, the compounds of this invention will exert a relativelyquick onset of action and have a prolonged duration of activity. Ingeneral, the compounds will exert their therapeutic effects at doselevels of about 0.25-250 mg/kg of body weight per day although, ofcourse, the degree of severity of the disease state, the age of thepatient and other factors determined by the attending diagnostician willinfluence the exact course and dosage regimen suitable for each patient.In general the parenterally administered dose of the active compounds isabout equivalent to that of the orally administered dose. The compoundshave been demonstrated to have a low potential for depressant or ataxicside effects.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose orcornstarch. In another embodiment, the compounds of general formula Ican be tableted with conventional tablet bases such as lactose, sucroseand cornstarch in combination with binders such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration, the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water, alcohols, oils and otheracceptable organic solvents, with or without the addition of asurfactant and other pharmaceutically acceptable adjuvants. Illustrativeof oils which can be employed in these preparations are those ofpetroleum, animal, vegetable, or synthesic origin, for example, peanutoil, soybean oil and mineral oil. In general, water, saline, aqueousdextrose and related sugar solutions, ethanol, glycols such as propyleneglycol or polyethylene glycol, or 2-pyrrolidone are preferred liquidcarriers, particularly for injectable solutions.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert material such as biodegradablepolymers or synthetic silicones, for example Silastic®, a siliconerubber manufactured by the Dow-Corning Corporation.

As is true in many classes of compounds with a pharmacological activityhaving a therapeutic end-use application, certain subgeneric groups andcertain specific members of the class, because of their overalltherapeutic index and their biochemical and pharmacological profile, arepreferred. In this instance the preferred compounds of formula I arethose wherein R₁, and R2 groups are methyl or ethyl, those wherein the Rsubstituent is chloro or fluoro, those wherein the R_(n) substituent isa monochloro or a monofluoro substituent, those wherein n is zero, thosewherein m is zero, and those compounds wherein Ar is phenyl.Specifically preferred compounds are:

4-methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole,

5-ethylsulfinyl-4-methyl-3-phenyl-4H-1,2,4-triazole,

5-ethylsulfonyl-4-methyl-3-phenyl-4H-1,2,4-triazole,

4-methyl-5-methylsulfinyl-3-phenyl-4H-1,2,4-triazole,

5-ethylthio-3-(2-fluorophenyl)-4-methyl-4H-1,2,4-triazole,

3-(2-fluorophenyl)-4-methyl-5-methylsulfonyl-4H-1,2,4-triazole,

3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole,

3-(2-fluorophenyl)-4-methyl-5-methylsulfinyl-4H-1,2,4-triazole,

3-(4-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole,

3-(2-chlorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole,

4-ethyl-3-(2-fluorophenyl)-5-methylthio-4H-1,2,4-triazole, and

5-ethylthio-4-methyl-3-phenyl-4H-1,2,4-triazole.

The following specific examples are given to illustrate the preparationof the compounds of this invention, although the scope of compoundsexemplified is not meant to be limiting, this being so in view of theease by which the compounds of formula I may be prepared by the generalmethods exemplified by employment of the necessary intermediates andsolvents.

EXAMPLE 1 1-(2-Fluorobenzoyl)-4-methylthiosemicarbazide

To a stirred room temperature suspension of 4-methylthiosemicarbazide(7.9 g, 7.5×10⁻² mole) and CHCl₃ (190 ml), 2-fluorobenzoyl chloride (9.4ml, 7.9×10⁻² mole) was added dropwise. After stirring overnight at roomtemperature, the precipitate was collected by filtration and the productwas washed with two portions of Et₂ O. Drying by suction gave acolorless powder which was used without further purification in thesubsequent cyclization step.

Alternate procedure

To a stirred room temperature solution of 4-methyl-thiosemicarbazide(10.5 g, 100×10⁻¹ mole) and pyridine (250 ml), 2-fluorobenzoyl chloride(11.9 ml, 1.00×10⁻¹ mole) was added dropwise. After stirring overnightat room temperature the excess pyridine was evaporated at reducedpressure first on a rotary evaporator and then at high vacuum. Thisafforded a mixture of the desired product and pyridine hydrochloridewhich is used without further purification in the subsequent cyclizationstep.

EXAMPLE 2 4-Methyl-1-(2-naphthoyl)thiosemicarbazide

To a stirred room temperature solution of 4-methyl-thiosemicarbazide(5.91 g, 5.62×10⁻² mole) and pyridine (150 ml) was added 2-naphthoylchloride (10.7 g, 5.61×10⁻² mole). After stirring overnight, thepyridine was evaporated at reduced pressure. The concentrate was treatedwith water and the undissolved product was collected by filtration anddried by suction. Crystallization from acetone/ethanol affordedoff-white needles, Mp 211° C. (decomp).

EXAMPLE 35-(2-Fluorophenyl)-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione

1-(2-Fluorobenzoyl)-4-methylthiosemicarbazide (11.3 g, 4.97×10⁻² mole)or the aforementioned mixture of the above and pyridine hydrochlorideand 1 molar aqueous NaHCO₃ (480 ml, 4.80×10⁻¹ mole) were stirred andheated to reflux. After refluxing overnight, the reaction was cooled inan ice bath before being acidified by the dropwise addition ofconcentrated hydrochloric acid (40 ml, 4.8×10⁻¹ mole). The resultingprecipitate was collected by filtration, washed with a little H₂ O, anddried by suction. This afforded a colorless powder. This material was ofsufficient purity to go on to the next step. If desired this materialcould be crystallized from EtOAc/hexane affording colorless needles, Mp137°-139° C.

EXAMPLE 4 2,4-Dihydro-4-methyl-5-(2-naphthyl)-3H-1,2,4-triazole-3-thione

4-Methyl-1-(2-naphthoyl)thiosemicarbazide (12.9 g, 4.97 ×10⁻² mole) and1 molar aqueous NaHCO₃ (480 ml, 4.80×10⁻¹ mole) were stirred and warmedto reflux. After refluxing overnight, the reaction was cooled in an icebath before being acidified by the dropwise addition of concentratedhydrochloric acid (40 ml, 4.8×10⁻¹ mole). The resulting product wascollected by filtration and dried by suction. Crystallization fromethanol afforded beige needles, Mp 223°- 225° C.

EXAMPLE 5 3-(2-Fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole

A mixture of5-(2-fluorophenyl)-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (4.56g, 2.18×10⁻² mole), K₂ CO₃ (3.01 g, 2.18×10⁻² mole), methyl iodide (1.5ml, 2.4×10⁻² mole), and acetone (65 ml) was stirred and warmed toreflux. After refluxing overnight, the solvent was evaporated and theconcentrate was treated with water. The aqueous mixture was extractedthree times with EtOAc. The EtOAc extracts were combined, washed withsaturated aqueous NaCl, and dried over anhydrous Na₂ SO₄. The dryingagent was removed by filtration and the filtrate was evaporated atreduced pressure affording a pale yellow oil which was purified bychromatography and kugel rohr distillation, affording a pale yellow oil:bp=190°-197° C. (0.3 mm).

EXAMPLE 6 4-Methyl-5-methylthio-3-(2-naphthyl)-4H-1,2,4-triazole

A mixture of2,4-dihydro-4-methyl-5-(2-naphthyl)-3H-1,2,4-triazole-3-thione (5.26 g,2.18×10⁻² mole), K₂ CO₃ (3.01 g, 2.18×10⁻² mole), methyl iodide (1.5 ml,2.4×10⁻² mole), and acetone (65 ml) was stirred and warmed to reflux.After refluxing overnight, the solvent was evaporated at reducedpressure and the concentrate was treated with water. The aqueous mixturewas extracted with EtOAc three times. The EtOAc extracts were combined,washed with saturated aqueous NaCl, and dried over anhydrous Na₂ SO₄.The drying agent was removed by filtration and the filtrate wasevaporated at reduced pressure to yield the desired product.Crystallization from Et0Ac afforded colorless plates, Mp 177°-179° C.

EXAMPLE 7 3-(2-Fluorophenyl)-4-methyl-5-methylsulfinyl-4H-1,2,4-triazole

To a stirred, 0° C., solution of3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole (5.0 g,2.2×10⁻² mole) and CH₂ Cl₂ (125 ml) was added portionwisem-chloroperoxybenzoic acid (4.83 g, 2.24×10⁻² mole, 80% active MCPBA).After stirring overnight at room temperature, the reaction was dilutedwith CH₂ Cl₂ until homogeneous and was then washed in turn twice withsaturated aqueous NaHCO₃ and once with saturated aqueous NaCl. Afterdrying over anhydrous Na₂ SO₄, the CH₂ Cl₂ was evaporated leaving an oilwhich slowly crystallized. Crystallization from EtOAc/hexane gave acolorless solid: Mp 95°-97° C.

EXAMPLE 8 4-Methyl-5-methylsulfinyl-3-(2-naphthyl)-4H-1,2,4-triazole

To a stirred, 0° C., solution of4-methyl-5-methylthio-3-(2-naphthyl)-4H-1,2,4-triazole (4.00 g,1.57×10⁻² mole) and CH₂ Cl₂ (110 ml) was added portionwisem-chloroperoxybenzoic acid (3.38 g, 1.57×10⁻² mole). overnight at roomtemperature the reaction was diluted with CH₂ l₂ (200 ml), washed twotimes with saturated aqueous NaHCO₃ and one time with saturated aqueousNaCl, and dried over anhydrous Na₂ SO₄. The drying agent was removed byfiltration and the filtrate was evaporated at reduced pressure leavingan off-white solid which was purified by flash chromatography (4% CH₃OH/CH₂ Cl₂). Crystallization from toluene afforded small colorlessplates: Mp 224°-226° C.

EXAMPLE 9 3-(2-Fluorophenyl)-4-methyl-5-methylsulfonyl-4H-1,2,4-triazole

To a stirred, 0° C., solution of 3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole (5.0 g, 2.2×10⁻² mole) and CH₂Cl₂ (125 ml) was added portionwise m-chloroperoxybenzoic acid (12.1 g,5.6×10⁻² mole, 80% active MCPBA). After stirring overnight at roomtemperature, the reaction was diluted with CH₂ Cl₂ until homogeneous andwas then washed in turn twice with saturated aqueous NaHCO₃ and oncewith saturated aqueous NaCl. After drying over anhydrous Na₂ SO₄, theCH₂ Cl₂ was evaporated at reduced pressure leaving a solid which waspurified by chromatography and subsequent crystallization fromEtOAc/hexane giving colorless matted needles: Mp 128°-130° C.

EXAMPLE 10 4-Methyl-5-methylsulfonyl-3-(2-naphthyl)-4H-1,2,4-triazole

To a stirred, 0° C., solution of4-methyl-5-methylthio-3-(2-naphthyl)-4H-1,2,4-triazole (5.62 g,2.20×10⁻² mole) and CH₂ Cl₂ (125 ml) was added portionwisem-chloroperoxybenzoic acid (12.1 g, 5.6×10⁻² mole, 80% active MCPBA).The reaction was stirred at 0° C. for 1 hour and then allowed to warm toroom temperature. After stirring overnight, the reaction was dilutedwith CH₂ Cl₂ until homogeneous. The CH₂ Cl₂ solution was then washed inturn with saturated aqueous NaHCO₃ and saturated aqueous NaCl. Afterdrying over anhydrous Na₂ SO₄, the CH₂ Cl₂ was evaporated at reducedpressure to afford the desired product, which was recrystallized fromethanol affording off-white plates, Mp 204°-206° C.

EXAMPLE 11 1-Benzoyl-4-methvlthiosemicarbazide

To a stirred solution of benzoic acid hydrazide (2.35 g, 1.73×10⁻² mole)and THF (50 ml) was added a solution of methyl isothiocyanate (1.14 g,1.56×10⁻² mole) and THF (50 ml). The reaction was then refluxed for 2hours before being cooled. The precipitate was collected by filtrationand crystallized from ethanol, affording a colorless solid, Mp 199°-200°C.

EXAMPLE 12 4-Methyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

A stirred mixture of 1-benzoyl-4-methylthiosemicarbazide (20.9 g,1.00×10⁻¹ mole) and 1 molar aqueous NaHCO₃ (1000 ml, 1 mole) was heatedto reflux. After refluxing overnight the reaction was cooled in an icebath. With stirring the solution was carefully acidified by the dropwiseaddition of conc. HCl (92 ml, 1.1 mole). A colorless precipitate formedand this was subsequently collected by filtration. Crystallization fromethanol afforded colorless, chunky crystals, Mp 164°-166° C.

Literature reference

G. Young and W. J. Oates, J. Chem. Soc., 79, G59 (1901).

EXAMPLE 13 4-Methyl-3-phenyl-5-methylthio-4H-1,2,4-triazole

To a stirred solution of4-methyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5.0 g,2.6×10⁻² mole) and 1 molar aqueous NaOH (59 ml, 5.9×10⁻² mole) was addeda solution of methyl iodide (2.6 ml, 4.2×10⁻² mole) and ethanol (13 ml).The reaction was stirred for 3 hours and it was then placed in therefrigerator. After standing in the refrigerator overnight, theprecipitate was collected by filtration. Crystallization fromisopropanol afforded colorless needles, Mp 134°-135° C.

Literature reference

E. Hoggarth, J. Chem. Soc., 1918 (1949).

EXAMPLE 14 4-Methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole

To a stirred, 0° C., mixture of4-methyl-3-phenyl-5-methylthio-4H-1,2,4-triazole (4.2g, 2.05×10⁻² mole)and CH₂ Cl₂ (120 ml) was added portionwise MCPBA (11.0 g, 5.1×10⁻² mole,80% active MCPBA). After 30 minutes, the cooling bath was removed. Afterstirring overnight the reaction was diluted with CH₂ Cl₂ (120 ml) andthe resultant mixture was transferred to a separatory funnel where itwas washed twice with saturated aqueous NaHCO₃ and once with saturatedaqueous NaCl. After drying over anhydrous Na₂ SO₄, the CH₂ Cl₂ wasevaporated at reduced pressure affording the crude product which waspurified by flash chromatography (20% EtOAc/CH₂ Cl₂) and crystallizationfrom EtOAc/hexane affording colorless crystals, Mp 158°-160° C.

By substituting the appropriate acid chlorides in the procedure ofExample 1 or by substituting the appropriate acid hydrazides andisothiocyanates in the procedure of. Example 11 and reacting theresulting thiosemicarbazide according to the procedures of Examples 3,5, 7 and 9, the tabulated compounds of Formula I are obtained.

    ______________________________________                                         ##STR6##                                                                     R.sub.n (Ar)(CH.sub.2).sub.m                                                                 q     R.sub.1  R.sub.2                                                                            mp (°C.)                            ______________________________________                                        phenyl         0     CH.sub.3 CH.sub.3                                                                           134-136                                    phenyl         1     CH.sub.3 CH.sub.3                                                                           144-146                                    phenyl         0     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           94-99                                      phenyl         1     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           131-133                                    phenyl         2     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           141-143                                    4-fluorophenyl 0     CH.sub.3 H    145-146                                    4-fluorophenyl 0     CH.sub.3 CH.sub.3                                                                           193-195                                    3-fluorophenyl 0     CH.sub.3 CH.sub.3                                                                           151-153                                    3-fluorophenyl 2     CH.sub.3 CH.sub.3                                                                           175-177                                    2-fluorophenyl 0     CH.sub.3 C.sub.2 H.sub.5                                                                    oil                                        2-fluorophenyl 0     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           95-97                                      2-fluorophenyl 1     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           63-67                                      2-fluorophenyl 2     C.sub.2 H.sub.5                                                                        CH.sub.3                                                                           145-147                                    2-chlorophenyl 0     CH.sub.3 CH.sub.3                                                                           oil                                        4-chlorophenyl 0     CH.sub.3 CH.sub.3                                                                           105-107                                    4-chlorophenyl 0     CH.sub.3 C.sub.2 H.sub.5                                                                    113-115                                    4-methoxyphenyl                                                                              0     CH.sub.3 CH.sub.3                                                                           149-151                                    4-methoxyphenyl                                                                              1     CH.sub.3 CH.sub.3                                                                           168-170                                    4-methoxyphenyl                                                                              2     CH.sub.3 CH.sub.3                                                                           187-189                                    4-tolyl        0     CH.sub.3 CH.sub.3                                                                           140-142                                    4-tolyl        1     CH.sub.3 CH.sub.3                                                                           161-163                                    4-tolyl        2     CH.sub.3 CH.sub.3                                                                           170-172                                    ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR7## wherein Ar isphenyl or naphthyl; R1 is C₁₋₋₆ lower alkyl;R2 is hydrogen or C₁₋₋₆alkoxy, hydroxy, halogeno or trifluoromethyl and n is zero, 1 or 2, orR_(n) --(Ar)-- is methylenedioxyphenyl; and m is zero, 1 or 2;or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein Ar is phenyl.
 3. A compound of claim 2 wherein m is zero.
 4. Acompound of claim 3 which is4-methyl-3-phenyl-5-ethylsulfinyl-4H-1,2,4triazole.
 5. A compound ofclaim 1 wherein n is zero or one, m is zero, R is halogeno, and R₁ andR₂ are independently methyl or ethyl.
 6. A compound of the formula##STR8## wherein Ar is phenyl or naphthyl;R₁ is C₁₋₋₆ lower alkyl; R₂ ishydrogen or C₁₋₋₆ lower alkyl; R is C₁₋₋₆ lower alkyl, C₁₋₋₆ alkoxy,hydroxy, halogeno, or trifluoromethyl, and n is zero, 1 or 2, or R_(n)--(Ar)-- is methyenedioxyphenyl; and m is zero, 1 or 2; or apharmaceutically acceptable salt thereof;with the provisos that (1)R_(n) --(Ar)--(CH₂)_(m) is other than 2-ethoxyphenyl); (2) when R_(n)--Ar--(CH₂)_(m) represents phenyl and R₁ represents methyl, R₂ is C₁₋₋₆lower alkyl; and (3) when R_(n) --(Ar)--CH₂)_(m) represents4-chlorophenyl, R₂ is other than ethyl.
 7. A compound of claim 6 whereinAr is phenyl.
 8. A compound of claim 7 wherein m is zero.
 9. A compoundof claim 8 which is4-methyl-3-phenyl-5-methylsulfonyl-4H-1,2,4-triazole.
 10. A compound ofclaim 8 which is 4-methyl-3-phenyl-5-ethylsulfonyl-4H-1,2,4-triazole.11. A compound of claim 6 wherein n is zero or one, m is one, R ishalogeno and R₁ and R₂ are independently methyl or ethyl.
 12. A compoundof claim 11 which is3-(2-fluorophenyl)-4-methyl-5-methylsulfonyl-4H-1,2,4-triazole.